Protective<i>Toxoplasma gondii</i>-Specific T-Cell Responses Require T-Cell-Specific Expression of Protein Kinase C-Theta

Nishanth, Gopala; Sakowicz-Burkiewicz, Monika; Händel, Ulrike; Kliche, Stefanie; Wang, Xiaoqian; Naumann, Michael; Deckert, Martina; Schlüter, Dirk

doi:10.1128/iai.01407-09

Cited by 14 publications

(13 citation statements)

References 50 publications

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“…Initially, cells of the innate immune system for instance dendritic cells, monocytes, macrophages and neutrophils are relevant for fi ghting against pathogens [33][34][35][36]. Further, the recruited dendritic cells function as a mediator between innate and adaptive immunity by recruiting T cells to the brain [37,38]. CD4+ and CD8+ T cells control parasite replication to prevent reactivation of the latent infection [39].…”

Section: Introductionmentioning

confidence: 99%

Spinal cord pathology in chronic experimentalToxoplasma gondiiinfection

Möhle¹,

Parlog²,

Pahnke³

et al. 2014

European Journal of Microbiology and Immunology

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Infection with the protozoan Toxoplasma (T.) gondii causes chronic infection of the central nervous system and can lead to lifethreatening encephalomyelitis in immunocompromised patients. While infection with T. gondii has long time been considered asymptomatic in immunocompetent hosts, this view is challenged by recent reports describing links between seropositivity and behavioral alterations.However, past and current researches are mainly focused on the brain during Toxoplasma encephalitis, neglecting the spinal cord as a key structure conveying brain signals into motion. Therefore, our study aimed to fill the gap and describes the spinal cord pathology in an experimental murine model of toxoplasmosis.In the spinal cord, we found distinct histopathological changes, inflammatory foci and T. gondii cysts similar to the brain. Furthermore, the recruitment of immune cells from the periphery was detected. Moreover, resident microglia as well as recruited monocytes displayed an increased MHC classes I and II expression. Additionally, the expression of pro-and anti-inflammatory cytokines was enhanced in the brain as well as in the spinal cord. In summary, the pathology observed in the spinal cord was similar to the previously described changes in the brain during the infection.This study provides the first detailed description of histopathological and immunological alterations due to experimental T. gondii induced myelitis in mice. Thus, our comparison raises awareness of the importance of the spinal cord in chronic T. gondii infection.

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Section: Introductionmentioning

confidence: 99%

Spinal cord pathology in chronic experimentalToxoplasma gondiiinfection

Möhle¹,

Parlog²,

Pahnke³

et al. 2014

European Journal of Microbiology and Immunology

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“…Despite limited access, the CNS is inundated by immune cells from the periphery during the chronic stage of T. gondii infection. The adaptive immune responses in the CNS have been extensively investigated, describing an important contribution to the local parasite control (22)(23)(24)(25). Besides, several studies have highlighted the function and phenotype of certain mononuclear cells such as microglia, brain DCs, and macrophages upon cerebral toxoplasmosis; however, the role of recruited newly described myeloid cell subpopulations remains undefined (19,26,27).…”

mentioning

confidence: 99%

Ly6Chigh Monocytes Control Cerebral Toxoplasmosis

Biswas

Bruder

Wolf

et al. 2015

The Journal of Immunology

100

125

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Cerebral infection with the parasite Toxoplasma gondii is followed by activation of resident cells and recruitment of immune cells from the periphery to the CNS. In this study, we show that a subset of myeloid cells, namely Ly6ChighCCR2+ inflammatory monocytes that infiltrate the brain upon chronic T. gondii infection, plays a decisive role in host defense. Depletion of this monocyte subset resulted in elevated parasite load and decreased survival of infected mice, suggesting their crucial role. Notably, Ly6ChighCCR2+ monocytes governed parasite control due to production of proinflammatory mediators, such as IL-1α, IL-1β, IL-6, inducible NO synthase, TNF, and reactive oxygen intermediate. Interestingly, Ly6ChighCCR2+ monocytes were also able to produce the regulatory cytokine IL-10, revealing their dual feature. Moreover, we confirmed by adoptive transfer that the recruited monocytes further develop into two distinct subpopulations contributing to parasite control and profound host defense. The differentiated Ly6CintCCR2+F4/80int subset upregulated MHC I and MHC II molecules, suggesting dendritic cell properties such as interaction with T cells, whereas the Ly6CnegF4/80high cell subset displayed elevated phagocytic capacity while upregulating triggering receptor expressed on myeloid cells-2. Finally, we have shown that the recruitment of Ly6Chigh monocytes to the CNS is regulated by P-selectin glycoprotein ligand-1. These results indicate the critical importance of recruited Ly6Chigh monocytes upon cerebral toxoplasmosis and reveal the behavior of further differentiated myeloid-derived mononuclear cell subsets in parasite control and immune regulation of the CNS.

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“…Additionally, the different genetic background of animals, namely C57B/6 in the previous [30][31][32] and 129/Sv in the recent [33] research work, might explain the divergent outcomes of Th17 experiments [34]. A pivotal importance of genetic environment for manifestation of PKCθ-knockout phenotype has also been observed previously in experiments with C57B/6 compared with BALBc mice [17]. These examples suggest that data generated under laboratory conditions with single in-breed mice strains might be potentially misleading.…”

Section: Pkcθ In Autoimmunity: New Light On Established Functionsmentioning

confidence: 73%

“…PKCθ -deficient mice, immunized with OVA peptide and re-challenged intranasally a week thereafter, were protected against adverse hypersensitivity responses to inhaled allergens [16]. Diminished GATA3 expression and down-regulation of Th2-specific cytokines was observed in the model of persistent Toxoplasma gondii infection in BALBc PKCθ − / − mice [17]. However, in this chronic inflammatory state mediated by both Th1 and Th2 immune responses, functionality of PKCθ − / − CD8 + T-lymphocytes appeared also to be affected.…”

Section: Pkcθ In Regulating T Helper Effector Phenotypementioning

confidence: 93%

“…Pronounced differences (death of PKCθ − / − mice compared with survival of wild-type controls) were observed only in the BALBc strain. C57BL/6 mice survived infections regardless of their distinct PKCθ genotype [17]. Data from mouse models of influenza and lymphocytic choriomeningitis virus (LCMV) infections provided further evidence that PKCθ is dispensable for induction of effective antiviral Th1 responses in vivo [5,18].…”

Section: Pkcθ In Regulating T Helper Effector Phenotypementioning

confidence: 98%

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Protein kinase Cθ: the pleiotropic T-cell signalling intermediate

Wachowicz

Baier

2014

Biochemical Society Transactions

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Activating as well as inhibitory circuits tightly regulate T-cell activation thresholds and effector differentiation processes enabling proper immune response outcomes. Recently, an additional molecular link between T-cell receptor signalling and CD4⁺ Th17 cell skewing has been reported, namely that protein kinase C (PKC) θ critically regulates Th17/Th1 phenotypic differentiation and plasticity in CD4⁺ T-cells by selectively acting as a 'reprogramming element' that suppresses Th1-typical genes during Th17-mediated immune activation in order to stabilize a Th17 cell phenotype.

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ProtectiveToxoplasma gondii-Specific T-Cell Responses Require T-Cell-Specific Expression of Protein Kinase C-Theta

Abstract: Protein kinase C-theta (PKC-) is important for the activation of autoreactive T cells but is thought to be of minor importance for T-cell responses in infectious diseases

Cited by 14 publications

References 50 publications

Spinal cord pathology in chronic experimentalToxoplasma gondiiinfection

Spinal cord pathology in chronic experimentalToxoplasma gondiiinfection

Ly6Chigh Monocytes Control Cerebral Toxoplasmosis

Protein kinase Cθ: the pleiotropic T-cell signalling intermediate

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